RESUMEN
8-Fluoroimidazo[1,2-a]pyridine has been established as a physicochemical mimic of imidazo[1,2-a]pyrimidine, using both in silico and traditional techniques. Furthermore, a novel synthesis of a 3,7-disubstituted-8-fluoroimidazopyridine 3 has been developed and the utility of the physicochemical mimicry has been demonstrated in an in vitro system. Here, the 8-fluoroimidazopyridine ring contained in ligand 3 acts as a bioisosteric replacement for imidazopyrimidine in the GABA(A) receptor modulator 2.
Asunto(s)
Regulación Alostérica/efectos de los fármacos , Agonistas del GABA/síntesis química , Agonistas de Receptores de GABA-A , Imidazoles/síntesis química , Piridinas/síntesis química , Animales , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Agonistas del GABA/química , Agonistas del GABA/farmacología , Humanos , Imidazoles/química , Imidazoles/farmacología , Ligandos , Ratones , Estructura Molecular , Piridinas/química , Piridinas/farmacología , Proteínas Recombinantes/agonistas , Relación Estructura-ActividadRESUMEN
Incorporation of fluorine at the 4-position of an existing series of sulfonyl piperidine 5-HT2A antagonists gave compounds with increased selectivity over the IKr potassium channel. This work led to the identification of 3b, a compound that gave no increase in QTc in the anesthetized dog up to plasma levels as high as 148 microM. Furthermore, 3b has been shown to increase slow-wave sleep bout duration and to decrease the number of awakenings in rats, indicating the potential utility of 5-HT2A antagonists in the treatment of insomnia.